Metalated Nitriles: Unmasking Fundamental Reactivity

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Non-technical AbstractIn this project, funded by the Chemical Synthesis Program of the Chemistry Division, the research team is exploring fundamentally new reactions of nitriles. The proposal has impact in several areas; the elevation of nitrile chemistry, student training and development, and improving the ability of students' writing. The research falls into three broad areas that will develop new reactions of nitriles for the synthesis of cyclic, carbon-based scaffolds of relevance for the synthesis of pharmaceuticals, agrochemicals, and new materials. The first third of the proposal focuses on an extremely rapid synthesis of bicyclic nitriles, the middle third develops counter-intuitive methods of creating new carbon-carbon bonds, and the last section of the proposal develops new routes to reactive nitrile intermediates to control the three dimensional shape of nitrile-substituted scaffolds. The project continues an excellent track record in training students and post-doctoral associates, particularly minorities and women, to provide a stream of bright, highly motivated students for careers in science. The approach features vigorous research training with synergistic mentoring of undergraduate and graduate students and an emphasis on career life balance through group educational events and annual professional development retreats. Improved writing skills are taught through a review writing strategy that transitions undergraduate and graduate students from novice learners to expert practitioners. The approach simultaneously addresses a general writing deficiency in many students while instilling tools to critically evaluate the primary literature. Publishing the strategy in the Journal of Chemical Education should allow others to replicate the strategy with other students.Technical AbstractThis project focuses on a blend of conceptually new bond constructions and new chemical entities, many of which challenge conventional processes. Preliminary results demonstrate the feasibility of preparing chiral decalones in a single synthetic operation, potentially replacing multi-step technology based on the Wieland-Miescher ketone. A highly unusual equilibration is under development which changes the stereochemistry of a quaternary bridgehead center; a process that challenges conventional notions. A counter-intuitive alkylation of metalated nitriles with unactivated alkenes is rapidly assembling tricyclic ketones. A complementary alkene addition uses S-ketenimines as particularly attractive nucleophiles to address two long-standing challenges: rapid access to stable ketenimine nucleophiles, and nitrile-based alkenylations. The last section of the proposal provides an orthogonal, innovative asymmetric alkylation with metalated nitriles. Collectively, the proposed research exploits the unique reactivity of nitriles consummate with the long-term objective of elevating metalated nitrile alkylations to a level of influence comparable to that of enolate alkylations.